CHEMOPREVENTION OF COLON CARCINOGENESIS BY DIETARY PERILLYL ALCOHOL

Epidemiological studies suggest that consumption of diets containing f ruits and vegetables, major sources of phytochemicals and micronutrien ts, may reduce the risk of developing cancer of the colon, Several phy tochemicals and micronutrients present in fruits and vegetables are kn own to exert cancer-chemopreventive effects in several organs, includi ng the colon, Monoterpenes such as d-limonene and perillyl alcohol der ived from orange peels and lavender, respectively, have been shown to possess chemopreventive properties against mammary, liver, and/or lung carcinogenesis, The present study was designed to investigate the eff icacy of dietary 40 and 80% maximum tolerated dose (MTD) levels of per illyl alcohol on azoxymethane (AOM)-induced colon carcinogenesis, The effect of this agent on the process of apoptosis in colon tumors was a lso investigated, Prior to the efficacy study, the MTD of perillyl alc ohol was determined in male F344 rats in a 6-week subchronic toxicity study and found to be a 2.5-g/kg diet when added to the AIN-76A diet. At 5 weeks of age, groups of male F344 rats were fed control (AIN-76A) diet or diets containing 1 and 2 g perillyl alcohol/kg diet, represen ting 40 and 80% MTD levels, respectively, At 7 weeks of age, all anima ls except those in the vehicle-treated groups were given two weekly s. c. injections of AOM (15 mg/kg body weight/week), All animals were con tinued on their respective dietary regimen for 52 weeks after AOM trea tment and then sacrificed. Colon tumors were evaluated histopathologic ally using routine procedures, Perillyl alcohol at the 1-g/kg level si gnificantly inhibited the incidence (percentage of animals with tumors ) and multiplicity (tumors/animals) of invasive adenocarcinomas of the colon, whereas perillyl alcohol at 2 g/kg diet inhibited the incidenc e of total adenocarcinomas of the colon and small intestine as compare d to the control diet. Our studies also indicate that the colon tumors of animals fed perillyl alcohol exhibited increased apoptosis as comp ared to those fed the control diet, These results demonstrate the pote ntial chemopreventive activity of perillyl alcohol against colon carci nogenesis, The chemopreventive activity of perillyl alcohol is mediate d through the tumor cell loss by apoptosis.